Changes in cardiac function reflect underlying changes in the content and organization of the muscle substrate. In the failing heart, these changes reflect interactions between myocyte and non-myocyte components of the heart. "Cross-talk between the myocardium, the vasculature and the non-myocyte cellular populations of the heart all may play a role in influencing cardiac pathogenesis. The development of fibrosis, or abnormal accumulations of extracellular matrix, is one ramification of this process. The presence of fibrosis in the failing heart has adverse effects on the structure and function of the myocardium. Increased levels of myocardial extracellular matrix alter ventricular stiffness, contribute to the risk of life threatening arrhythmias and may promote the progressive deterioration of contractile function. We propose to determine if fibrosis plays a significant role in the development of progressive cardiac dysfunction in a transgenic mouse model of hypertrophy and early failure. We have developed a transgenic mouse model for hypertrophic cardiomyopathy (HCM) through cardiac specific expression of a mutant myosin heavy chain (Vikstrom et al., 1996). These animals exhibit the histopathologic features of human HCM, including myocellular disarray, fibrosis and the presence of abnormal small coronary vessels. In this model, females continue to hypertrophy while males progress from a hypertrophied to a dilated phenotype concomitant with increased fibrosis. The HCM mice should prove to be useful for identifying changes in cardiac gene expression during chronic cardiac hypertrophy and the development of early heart failure, including those changes that provoke fibrosis. Our analysis will consist of three branches. i) We will evaluate the role of TGFbeta1 and angiotensin-converting enzyme (ACE) gene expression in the HCM mouse heart and determine the spatial and temporal patterns of their expression with respect to the development of fibrosis. ii) We will determine the ramifications of myocardial fibrosis on contractile function and electrical conduction in the isolated mouse heart. iii) We will determine the requirement for ACE expression in the development of fibrosis through genetic cross-breeding experiments. Our goal is twofold. 1) use the HCM mice as a tool for assessing the molecular and functional implications of fibrosis in the heart and 2) develop new analytical approaches for studying gene expression and electrical conduction in the mouse heart.